Multiparameter MRI assessment of metformin and exercise effects on skeletal muscle in prediabetes: a randomized controlled trial.

BACKGROUND: The metabolic effects of combined metformin and aerobic exercise on skeletal muscle in prediabetes remain unclear. We evaluated individual and combined effects on skeletal muscle metabolism using multiparameter magnetic resonance imaging (MRI) and assessed prediabetes remission. MATERIALS AND METHODS: In this 12-week randomized controlled trial, forty-two prediabetic adults aged 48.4 ± 13.1 years mean ± standard deviation) were randomized into control (n = 10), metformin (n = 10), exercise (n = 11), and combined therapy (n = 11) groups. Multiparameter MRI measured T2, apparent diffusion coefficient (ADC), fractional anisotropy (FA), intermuscular adipose tissue (IMAT), intramyocellular lipids, visceral adipose tissue (VAT), and muscle cross-sectional areas (MSCAs). Blood biomarkers were assessed by standard protocols. Analyses included ANOVA, Fisher's exact test, and correlation analysis. RESULTS: Normoglycemia occurred in 90% of the combined group, 80% of the exercise, 20% of the metformin, and 10% of the controls. Exercise alone significantly decreased IMAT%, T2, and ADC, and increased FA, whereas metformin alone had no significant effects. Combination therapy did not further improve blood biomarkers or change MRI parameters versus exercise, but uniquely reduced VAT and increased MSCAs. IMAT% reduction was borderline greater in subjects with high baseline IMAT after combination therapy (p = 0.051). MRI parameters, particularly IMAT%, T2, and FA, correlated with fasting glucose, incremental area under the curve of glucose and insulin, and hemoglobin A1c. CONCLUSION: Aerobic exercise favorably altered skeletal muscle tissue characteristics and metabolic markers in prediabetes. Metformin did not attenuate these effects and may enhance IMAT reduction in subjects with high baseline IMAT. RELEVANCE STATEMENT: Multiparameter MRI provides a sensitive, noninvasive means to quantify skeletal muscle composition and function in prediabetes, enabling precise assessment of the metabolic effects of combined lifestyle and pharmacological interventions. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2300072162), retrospectively registered on June 5, 2023. KEY POINTS: Aerobic exercise improves muscle composition and glucose metabolism in prediabetes. Metformin adds benefits for reducing muscle fat in high-fat individuals. Multiparameter MRI enables noninvasive monitoring of skeletal muscle metabolic changes.